Diagnostic and Treatment Strategies for Preclinical HCM

临床前 HCM 的诊断和治疗策略

• 批准号: 6854423
• 负责人: Carolyn Y Ho
• 金额: $ 16.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-26 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6854423
• 关键词: asymmetric septal hypertrophy; biomarker; blood tests; calcium channel blockers; cardiovascular disorder chemotherapy; cardiovascular disorder diagnosis; cardiovascular disorder prevention; cardiovascular disorder risk; clinical research; clinical trials; diltiazem; drug screening /evaluation; early diagnosis; echocardiography; gadolinium; genetic disorder diagnosis; heart contraction; heart imaging /visualization /scanning; human subject; human therapy evaluation; hypertrophic myocardiopathy; longitudinal human study; magnetic resonance imaging; patient oriented research; sarcomeres

DESCRIPTION (provided by applicant): Hypertrophic cardiomyopathy (HCM), an autosomal dominant disorder characterized by histopathologic findings myocyte disarray and fibrosis, has clinical manifestations of unexplained left ventricular hypertrophy (LVH), diastolic dysfunction, and an increased risk for sudden death. It is a common genetic cardiovascular disorder, affecting approximately 1 in 1000 individuals in the general population. The identification of sarcomere gene mutations as the molecular basis of HCM differentiates this disorder from other types of inherited or secondary causes of LVH. Despite increasingly sophisticated understanding of the causal genetic defects, the precise phenotypic manifestations remain relatively poorly understood. Collaborative basic science and human clinical studies to define the full spectrum of the HCM phenotype are required before molecular discoveries can be effectively translated into the practical management of disease. Genetic-based diagnosis allows for early identification of individuals at risk for developing HCM, prior to the expression of typical clinical manifestations (e.g. LVH). Greater understanding of the preclinical phase of this condition may ultimately inspire rational treatment strategies that will move from contemporary symptom palliation to altering the natural history of disease. Precise identification of early clinical markers of genetic disease will also provide benchmarks for monitoring treatment efficacy. This 2-part longitudinal study proposes to examine and manipulate the early stages of HCM. First, a genotype-positive preclinical population will be examined to detect early alterations in contractile function and myocardial architecture incorporating serial echocardiography with Doppler tissue and strain analysis, gadolinium-enhanced cardiac magnetic resonance imaging, and assessment of serum biomarkers of hemodynamic stress. Second, a pilot interventional trial will be performed to assess the tolerability and efficacy of diltiazem treatment of this preclinical population in improving parameters of diastolic function and to serve as the basis for future larger-scale trials of efficacy.

描述（由申请人提供）： 肥厚型心肌病 (HCM) 是一种常染色体显性遗传疾病，其特征是组织病理学发现心肌细胞紊乱和纤维化，临床表现为不明原因的左心室肥厚 (LVH)、舒张功能障碍和猝死风险增加。它是一种常见的遗传性心血管疾病，影响普通人群中大约千分之一的人。肌节基因突变作为 HCM 的分子基础，将这种疾病与其他类型的遗传性或继发性 LVH 原因区分开来。尽管对因果遗传缺陷的了解越来越复杂，但对精确的表型表现仍然知之甚少。在将分子发现有效转化为疾病的实际管理之前，需要基础科学和人类临床合作研究来定义 HCM 表型的全谱。基于基因的诊断可以在出现典型临床表现（例如 LVH）之前早期识别出有发生 HCM 风险的个体。对这种疾病的临床前阶段的更多了解可能最终会激发合理的治疗策略，从缓解当代症状转向改变疾病的自然史。遗传病早期临床标志物的精确识别也将为监测治疗效果提供基准。这项由两部分组成的纵向研究旨在检查和操纵 HCM 的早期阶段。首先，将检查基因型阳性的临床前人群，以检测收缩功能和心肌结构的早期变化，结合连续超声心动图与多普勒组织和应变分析、钆增强心脏磁共振成像以及血流动力学应激的血清生物标志物评估。其次，将进行一项试点介入试验，以评估地尔硫卓治疗该临床前人群在改善舒张功能参数方面的耐受性和有效性，并作为未来更大规模疗效试验的基础。